Development of a Treatment to Improve Arteriovenous Fistula Function

Project Summary/Abstract: In 2017, there were ~750,000 US patients with end-stage kidney disease (ESKD) who required chronic hemodialysis (HD). The ESKD population in the USA is increasing at the rate of 3% per year. Vascular access through an arteriovenous fistula (AVF) is required for optimal HD and clearance of uremic toxins. The patency

of AVFs at one year is estimated to be only 62%. Venous stenosis, which occurs because of venous neointimal hyperplasia (VNH), is responsible for the majority of AVF failures. Over three billion dollars are spent annually to maintain the function of hemodialysis AVFs. There are no therapies which can prevent AVF VS. Effective, non-

invasive methods that reduce AVF venous stenosis would be of tremendous benefit to patients with ESKD. Pavaj Vascular is developing and commercializing a novel therapy that can prevent AVF venous stenosis. We have published data showing that VS/VNH in AVF is associated with increased expression of immediate early

response genes (Iex-1/Ier3) in clinical specimens with failed HD AVFs. Experimentally, Iex-1-/- mice (genetic engineered animals that lack Iex-1) with AVFs have less VS/VNH than control mice. Iex-1 expression is down- regulated by the calciotropic hormone, 1,25(OH)2D3 (1,25), the active form of Vitamin D3, which is used in CKD

patients for calcium homeostasis. Oral administration of 1,25 vitamin D3 does not reduce AVF VS and does cause hypercalcemia. Adventitial delivery of nanoparticles composed of poly (lactic-co-glycolic acid (PLGA) encapsulated with 1,25(OH)2D3 (1,25 NP) in a thermosensitive hydrogel to the AVF outflow vein reduces VS/VNH

in mice and pigs with chronic kidney disease (CKD) without hypercalcemia. Furthermore, we have shown that in mice and pigs, adventitial delivery of 1,25 NP reduces Iex-1 expression and increases blood flow by reducing VNH. These data suggest that 1,25 NP may be a useful treatment for improving maturation and preventing

VS/VNH in AVF. Pavaj Vascular will use the direct phase II SBIR to complete two main goals: 1) Evaluate the Stability and Biocompatibility of GMP grade 1,25 NP. 2) Determine the long-term efficacy of 1,25 NP on reducing AVF VS/VNH using a porcine model with CKD. Successful completion of this proposal will allow us to obtain data needed to apply for FDA Investigational New

Drug (IND) approval to perform First in Man studies to evaluate this promising technology. .